Small molecules that increase the conversion of food to body weight gain

ABSTRACT

The present invention relates to peptide-like compounds, e.g. aminocarboxylic acid amide derivatives, and to methods of using same in the field of general health care, for example, to improve resistance to stress, improve production of desired characteristics or useful products in animals, to increase weight gain, prevent diseases caused by pathogens, and to decrease feed efficiency. The invention has applications in the field of animal husbandry, and in treating or preventing weight loss associated with a disease in humans. It also relates to administering carbobenzoxy beta-alanyl taurine to improve feed efficiency in an animal, comprising administering to the animal an amount of carbobenzoxy beta-alanyl taurine sufficient to reduce the amount of food required to increase a unit of weight in the animal.

This application is a continuation in part of U.S. Ser. No. 09/256,763,filed on Feb. 24, 1999 now 6,166,086, and it claims priority to U.S.Provisional Application Nos.: 60/075,966 filed Feb. 24, 1998 and60/085,474 filed May 14, 1998, all of which are incorporated herein byreference in their entirety.

FIELD OF THE INVENTION

The present invention relates to peptide-like compounds, e.g.aminocarboxylic acid amide derivatives, and to methods of using same inthe field of general health care, for example, to improve resistance tostress, improve production of desired characteristics or useful productsin animals, to increase weight gain, and to decrease feed efficiency.The invention has applications in the field of animal husbandry.

BACKGROUND OF THE INVENTION

In the area of animal husbandry, antimicrobials, includingantibacterials, are used routinely for prophylaxis, chemotherapy andgrowth promotion. Animals receiving antibiotics in their feed, gain fourto five percent more body weight than animals that do not receiveantibiotics. They are important for sustainable livestock production andfor the control of animal infections that could be passed on to humans.However, microbiological and clinical evidence is mounting thatresistant bacteria or resistance determinants might be passed fromanimals to humans, resulting in human infections that are more difficultto treat. With a marked increase in the prevalence and distribution ofantimicrobial-resistant infections in hospitals and the community thequestion has been raised as to how this escalation of resistance couldhave been influenced by the use of antimicrobials in livestockproduction.

Antimicrobials are used extensively in livestock, fish and plantproduction. Most are administered to livestock animals in subtherapeuticdoses as growth promoters which boost the utilization of the geneticpotential for growth of pigs and poultry, improve feed conversion andreduce waste production output from intensive livestock production. Theyare also used prophylactically to prevent diseases, for example, aftercommingling of animals from different farms, or among animals raised incrowded conditions with thousands of animals living under confinement ona single premises.

Antimicrobial use leads to the selection of resistant forms of bacteriain the ecosystem of use. Low level, long-term exposure to antimicrobialsmay have a greater selective potential than short-term, full-dosetherapeutic use because full doses are more likely to kill all of thetargeted bacteria in the host, making it less likely that resistantbacteria will emerge. Adverse consequences of selecting resistantbacteria include an increase in the prevalence of resistant bacteria inanimals, causing diseases that won't respond to known antimicrobials;the transfer of resistant pathogens to humans via direct contact withanimals, or through the consumption of contaminated food or water; thetransfer of resistance genes to human bacteria; an increase in theincidence of human infections caused by resistant pathogens; andpotential therapeutic failures in animals and humans.

Antibiotic resistance that arises in animal husbandry affects suchzoonotic pathogens as Salmonella serovars and Campylobacter, both ofwhich are associated with diarrheal diseases, and human and animalcommensals such as Escherichia coli and enterococci. Because the humanand animal microbial ecosystems are inextricably intertwined, microbialantibiotic resistance readily crosses boundaries so that antibioticsgiven to animals and closely related antibiotic compounds used in humantherapy have been exerting selective pressure on their target bacteriafor decades.

Specifically, the introduction of fluorquinolones for use in poultrycaused a dramatic rise in the prevalence of fluoroquinolone-resistantCampylobacter jejuni isolated in live poultry, poultry meat and frominfected humans. The use of avoparcin as a growth-promoting feedadditive for pigs and poultry has contributed to the reservoir oftransferable resistance genes to glycopeptides, including vancomycin, inthe commensal enterococci of animals. Multiresistant Escherichia colihave been selected by use of broad spectrum antimicrobials in bothlivestock and humans.

The problems caused by the prolific use of a wide variety ofantimicrobials in animal husbandry is a driving force for thedevelopment of antibiotic resistance in certain pathogenic bacterialspecies. The problems of resistance reach beyond the country of originbecause meat products are traded worldwide.

DRAWINGS

FIG. 1 shows specific TAUROX™ compounds of the invention.

SUMMARY OF THE INVENTION

The present invention is therefore directed to a nontoxic,non-antimicrobial agent that can replace or supplement the use ofantibiotics in the animal husbandry of livestock animals to increasehealth and general well-being, productivity, feed efficiency and weightgain. The present invention is also directed to such an agent thatincreases the vitality of livestock animals as is indicated by theirability to withstand environmental stressors such as wide variations intemperature, food deprivation which can occur under crowded conditions,and exposure to pathogenic bacteria and viruses.

DETAILED DESCRIPTION OF THE INVENTION

In order that the present invention may be fully understood thefollowing detailed description is set forth.

The invention describes a variety of small molecules that improve healthand general well-being, increase body weight, lower feed efficiency, andhelp animals overcome environmental stress such as exposure toinfection, temperature change, and/or food deprivation.

This invention relates to the use of many kinds of small molecules,including beta-alethine, a naturally occurring disulfide, to (1) improvegeneral health and well being; (2) increase the ability of an animal toresist environmental stressors, including temperature change, fooddeprivation, and exposure to pathogenic bacteria and viruses; (3)increase the production of desired characteristics or useful productsfrom animals, (4) increase weight gain, or (5) decrease feed efficiencyin animals. The present invention also relates to the use of smallmolecules, including beta-alethine, to decrease mortality duringshipping or transport of livestock. Other compounds, structurallysimilar to beta-alethine, including both disulfides and thiols, are alsowithin the present invention. TAUROX™ compounds (described in U.S. Ser.No. 08/733,174), and small molecules having immunoregulatory isomerssuch as mevalonate and mevalonolactone (described in U.S. Pat. No.5,849,777 and 5,783,594, and U.S. Serial No. 09/033,098 which areincorporated in their entirety by reference) can also be used for thevarious embodiments of the present invention.

Beta-alethine and TAUROX™ compounds have the Formula I:

wherein:

-   -   A is a group of the formula —PO₃H, —SO₃H, —OPO—(OH)₂, —OSO₂OH,        or —SH, or pharmaceutically acceptable salt thereof or        physiologically hydrolyzable derivative thereof, or disulfide        thereof when A is —SH. Suitable salts include sodium, potassium,        calcium and zinc. Suitable hydrolyzable derivatizing groups        include esters, such as substituted or unsubstituted lower alkyl        (e.g. C₁ to C₄) or arylalkyl (e.g. benzyl) esters;

R₁ is H, a linear or branched lower alkyl, for example, a C₁ to C₆alkyl, arylalkyl, for example, wherein the alkyl moiety is C₁ to C₄alkyl and the aryl moiety is a substituted (eg lower alkyl or halogen)or unsubstituted phenyl group, or alkenyl (for example, C₂-C₆ alkenyl);

R₂ is H, a linear or branched lower alkyl, for;example, a C₁ to C₆alkyl, an alkenyl, for example, a C₂-C₆ alkenyl, an arylalkyl, forexample, wherein the alkyl moiety is a C₁ to C₄ alkyl and the arylmoiety is a substituted (eg lower alkyl or halogen) or unsubstitutedphenyl group; or an acyl, for example, acetyl, benzoyl, arylsulfonyl(for example, when the aryl moiety is phenyl); a carbonate ester such asalkoxycarbonyl (e.g., C₁-C₇ alkoxy carbonyl) (for example, —OCOC(CH₃)₃);allyloxy carbonyl (e.g. —OCOCH₂CH═CH₂); cycloalkoxycarbonyl (e.g. whenthe ring is C₃-C₈ (C₅-C₆ being preferred) and when the alkoxy moiety isC₁-C₈) (for example —OCOCH₂C₅H₉); or an unsubstituted arylalkoxycarbonyl(for example —OCOCH₂C₆H₅) or a substituted arylalkoxycarbonyl whereinthe substituent is, for example, a halogen, a nitro group, an aminogroup or a methoxyl group;

-   -   alternatively, R¹ and R² taken together form, with the nitrogen        to which they are attached, a 5 to 7 membered ring (for example,        R¹ and R² taken together can be —(CH₂)₄—, —(CH₂)₅ or —(CH₂)₆—);        and    -   L¹ and L² are hydrocarbon linking groups, for example, a linear        or branched chain alkyl of the formula —(C_(n)H_(2n))—wherein n        is, for example, 1 to 8 in the case of L¹ and 2 to 8 in the case        of L² except when A is —PO₃H or —SO₃H in which case n can be        1-8, a cycloalkyl of 3 to 8 carbon atoms, preferably 5 or 6        carbon atoms; or an interphenytene

Advantageously, L¹ and L² are —(C_(n)H_(2n))— wherein n is 1 to 8 in thecase of L¹ or 2 to 8 in the case of L² except when A is —PO₃H or —SO₃Hin which case n can be 1-8 (examples of branched chain alkyls include—CH₂CHR—, —CH₂CHRCH₂—, —CHRCH₂CH₂—, and —CH₂CH₂CHR—wherein R is an alkylgroup and wherein the total number of carbon atoms, including R, doesnot exceed 8).

A particular group of compounds of the invention is of the formula (I)wherein A, R¹, R², L¹ and L² are as defined above in said firstembodiment with the proviso that when A is —SO₃H or pharmaceuticallyacceptable salt thereof or physiologically hydrolyzable derivativethereof, one of R¹ and R² is H, and L¹ and L² are (CH₂)₂, then the otherof R¹ and R² is not H.

Another particular group of compounds of the invention is of the formula(I) wherein A, R¹, R², L¹ and L², are as defined above in the firstembodiment with the proviso that when A is —SO₃H or pharmaceuticallyacceptable salt thereof or physiologically hydrolyzable derivativethereof, one of R¹ and R² is H, and L¹ and L² are (CH₂)₂, then the otherof R¹ and R² is not C₆H₅CH₂OCO—.

A further particular group of compounds of the invention is of theformula (I) wherein A is a group of the formula —PO₃H or —OPO(OH)₂, moreparticularly —PO₃H, or a pharmaceutically acceptable salt thereof or aphysiologically hydrolyzable derivative thereof, and wherein R¹, R², L¹,and L² are as defined above in the first embodiment.

Another particular group of compounds of the invention is of the formula(I) wherein A is a group of the formula —SO₃H or —OSO₂OH, moreparticularly —OSO₂OH, or pharmaceutically acceptable salt thereof, orphysiologically hydrolyzable derivative thereof, and wherein R¹, R², L¹and L² are as defined above in the first embodiment. The provisos abovecan apply to this group of compounds as well.

A further particular group of compounds of the invention is of theformula (I) wherein at least one of R¹ and R² is an alkyl,advantageously a lower alkyl (eg C₁ to C₆), and wherein A, L¹, L² andthe other of R¹ and R² are as defined above in the first embodiment.

Another particular group of compounds of the invention is of the formula(I) wherein R¹ is an alkyl and R² is acyl and wherein A, L¹ and L² areas defined above in the first embodiment.

A further particular group of compounds of the invention is of theformula (I) wherein L¹ is —(CH₂)—and wherein A, R¹, R², and L² are asdefined above in the first embodiment.

Yet another particular group of compounds of the invention is of theformula (I) wherein R¹ and R² are taken together and form, with thenitrogen to which they are attached, a 5 to 7 membered ring, and whereinA, L¹ and L² are as defined above in the first embodiment.

The various TAUROX™ compounds of formula I are shown in FIG. 1. Theyare: TAUROX™ S: Beta-alanyltaurine or Beta-alanyl-2-aminoethylsulfonicacid, TAUROX™ SB: [Zinc] Carbobenzyloxy-beta-alanyltaurine, or [Zinc]carbobenzyloxy-beta-alanyl-2-aminoethylsulfonic acid, TAUROX™ OS:Beta-alanylethanolamine 0-sulfate, TAUROX™ BOS: [Zinc]carbobenzyloxy-beta-alanylethanolamine O-sulfate, TAUROX™ OP: [ Zinc]Beta-alanylethanolamine O-phosphate, TAUROX™ BOP: [Zinc]Carbobenzyloxy-beta-alanylethanolamine O-phosphate, TAUROX™ P: [Zinc]Beta-alanyl-2-aminoethylphosphonic acid, and Tarox™ BP: [Zinc]Carbobenzyloxy-beta-alanyl-2-aminoethylphosphonic acid.

The present compounds can also be present covalently bound to proteins,for example, antigens or other immunologically active proteins, or celltargeting proteins. Such conjugates can be synthesized using techniquesknown in the art.

The compounds of the present invention can be prepared using, forinstance, methods provided in the Examples and in U.S. Pat. No.4,102,948 and U.S. Pat. No. 4,218,404, as appropriate.

The disulfide beta-alethine, and beta-aletheine (the correspondingthiol) have a variety of diverse effects including use as a nontoxicanti-cancer agent, the ability to delay senescence in vivo and in vitro,and to facilitate the adaptation and differentiation of cultured cells.Knight et al., U.S. Pat. No. 5,643,966, and U.S. application Ser. Nos.08/346, 177, 08/468,043, and 08/468,041, which are incorporated hereinby reference for all purposes. Beta-alethine has also been reported tobe an adjuvant that stimulates antigen-specific immunoglobulinsynthesis. (08/733,174 incorporated herein by reference).

In a first embodiment, it was discovered that small molecules of thepresent invention, enhanced the ability of animals to withstandenvironmental stressors. To test the effects of beta-alethine on theability of animals to withstand environmental stress, experimentalchicks received a single injection of beta-alethine on the day of thehatch, which was day one of an 18 day experiment. On day 8, a Newcastledisease live virus vaccine was administered. On Day 11, the chicks werestress by simultaneous food withdrawal, temperature extremes, andaerosol exposure to E. coli 19B. Temperature stress continued throughday 14. On day 18, all pens of chicks, were evaluated for weight gainand feed efficiency, adjusting for dead chicks; mortality was observedthroughout the study.

Beta-alethine decreased mortality as early as day seven, and mortalitycontinued to be lower in beta-alethine-treated chicks through day 16 ofthe experiment in two pens and throughout the entire study in the otherpen. Beta-alethine enhanced the ability of chicks to surviveenvironmental stressors that are commonly encountered in poultry houseswhere chickens are commercially raised in large numbers and aretherefore routinely exposed to pathogenic viruses and bacteria. It isalso possible that beta-alethine's ability to act as an adjuvant tostimulate an antigen-specific immune response to pathogens may havecontributed to the decrease in mortality of chicks exposed to E. coliantigen.

In a most preferred embodiment, approximately 50 ng/kg beta-alethine isadministered to an animal to decrease mortality from environmentalstressors and/or to enhance the ability of the animal to tolerate fooddeprivation or temperature extremes, and/or to enhance the likelihoodthat the animal will survive exposure to pathogenic viruses or bacteria.In another preferred embodiment, beta-alethine is administered at a doseof from about 200 pg to about 20 mg per kilogram.

It is emphasized that the small molecules in the embodiment of thepresent invention can be administered at any time during the life of theanimal, and periodic administrations throughout the life of the animalare anticipated to achieve the optimum benefit from the drug. In onepreferred embodiment, the compounds of Formula I are injected in ovo. Inanother embodiment, the drugs are injected shortly after hatchadministered by one of a variety of routes known in the art ofveterinary medicine and animal husbandry and periodically thereafter.

One embodiment of the present invention is directed to multipleadministrations of Formula I compounds or other small molecules duringthe life of the animal. A particularly important time to administer drugis shortly before livestock animals such as cattle, pigs, sheep, fish,shrimp, shellfish and goats, are transported from one location toanother in order to increase vitality of the animals and their abilityto survive the stress of crowded conditions, exposure to pathogens,deprivation of food and water, and temperature changes. The use of thedrugs disclosed herein to enhance the ability of an animal to withstandenvironmental stress includes human travel, shipment of cows, turkeysand other food or pet animals or desirable or valuable animals of alltypes, between sites used to rear or house them, weaning of animalsincluding pigs, and farming of land animals and of tank and “open water”raising of fish and shellfish. It has also been discovered smallmolecules, including beta-alethine increase the ability of an animal tocombat external stress including stress imposed by chemical agents, alltypes of radiation, natural toxin, and all manner of infectious agents.In addition to protecting whole animals from internal and externalstress, specific organs such as brains, skin, heart, liver and othervital tissues are protected from loss of mass and the adverse effects ofstress or bacterial or viral disease. Animals (including but not limitedto humans, livestock animals, chickens, birds, mammals, reptiles,shrimp, fish and shellfish) are frequently exposed to normal stress ofgrowth and development and specific stress such as viral exposure and/orbacterial exposure. It has further been discovered that the compoundsdisclosed herein increase body weight and lower feed efficiency (i.e.,the amount of feed required for weight gain) thus multiple uses inanimal husbandry, and food production are discovered. Reduction ofdisability, stress induced illness, weight loss is advantageous atvarious times including but not limited to the treatment and/orprevention of loss of weight and life when animals are shipped andstressed including human travel, shipment of cows, turkeys and otherfood or pet animals between sites used to rear or house them, weaning ofanimals including pigs, and farming of land animals and of tank and“open water” raising offish and shellfish.

The present invention is not limited to beta-alethine; molecules thatare structurally or functionally similar to beta-alethine can also beused to accomplish the objectives of the present invention. The use ofdisulfides, thiols, TAUROX™ compounds such as TAUROX™-SB and otheramino-peptide like compounds disclosed in U.S. Ser. No. 08/733,174 whichissued as U.S. Pat. No. 6,007,819, can also be used for the embodimentsdescribed herein. Small molecules having isomers such as mevalonate andmevalonolactone (described in U.S. Pat. No. 5,849,777 and 5,783,594, andU.S. Ser. No. 09/033,098 which are incorporated in their entirety byreference).

It was discovered that beta-alethine has a positive effect on weightgain and on lowering feed efficiency in animals by significantlyincreasing conversion of feed to weight; thus multiple uses in animalhusbandry and food production are discovered. The results of oneexperiment using highly stressed male Peterson×Hubbard broiler chicks,show that the feed efficiency ratio of the beta-alethine-treated groupwas 7.9% lower relative to the negative controls. In a second studyusing a normal flock of Avian×Ross broiler chicks, an average decreasein feed efficiency ratios of about 4%. Therefore, another embodiment ofthe present invention is the use of beta-alethine or functionally orstructurally similar compound, or other small molecules disclosed hereinto decrease feed efficiency values.

The deliverable weight ratio is similar to feed efficiency, but itincludes an adjustment for the food consumed (and wasted) by chicks thatdo not survive. Experimental results show that beta-alethine caused a10.8% improvement in final deliverable weight ratio (lower values)relative to controls. Therefore, another embodiment of the presentinvention is the use of beta-alethine or structurally similar orfunctionally similar molecule, to increase deliverable weight ratios inlivestock animals or other animals including birds, fish, shellfish,bovine, porcine, and goats. The compounds can also by administered toanimals to increase milk production, or to enhance production of othervaluable or desirable characteristics such as improving fur, hooves,feathers, and so on. The compounds, especially beta-alethine andTAUROX-SB (carbobenzoxy-beta-alanyl taurine) are useful in any animalraised as a pet or for food or to produce a desired product, includingmilk, wool, caviar, feathers, nails, fur, hooves. Increase products evenif not increase efficiency.

In another embodiment, small molecules, including beta-alethine, areadministered to humans or other animals suffering fromdisease-associated weight loss in order to increase weight gain and/orto improve the utilization of food by increasing the conversion of foodto body weight. Such illnesses include anorexia nervosa, AIDS, cachexia,Crohn's disease, or other illnesses or situations where thepatient/animal ingests less food, or absorbs the nutrients from the foodless efficiently than is desired. These compounds can also be used totreat underweight animals including humans, who do not have a disease,in order to increase body weight and/or the conversion of food to bodyweight. The compounds can be administered for this purpose at dosesranging from the picogram range to the miligram range, as needed, up tothe maximum tolerated dose. Acceptable doses can be determined usingroutine practices.

In one embodiment, beta-alethine is administered at relatively low dosesonce every 14 days or on a daily basis over extended periods of time toraise or maintain body weight, for example in relatively normalpopulation including elderly, young or the sick. Alternatively, forexample in a crisis situation, beta-alethine is administered at higherdoses as needed and the amount administered is manipulated based on theresponse of the recipient.

The compounds of Formula I for use in the various embodiments of thepresent invention can be administered as needed by observing standardindicia of the progress of the disease using methods known to persons ofordinary skill in the art. The drugs are preferably administered on adaily or alternate-day regimen as described more fully below, until thelo desired results are achieved. Other regimens, such as weekly orbiweekly regimens may suffice, particularly when a positive response isreadily apparent. Decreases in dosages of the drugs, the frequency ofadministration, or both, can be made as normalization progresses. Themethods of the present invention are not limited to any particularamount of the above-identified drugs, as therapeutically effectiveamounts can be determined by routine testing.

The compounds of the present invention are typically used in the form ofa pharmaceutical composition comprising one or more compounds of FormulaI, or salt or hydrolyzable derivative thereof, together with apharmaceutically acceptable or feed acceptable diluent or carrier. Thecompositions of the present invention are also so formulated. Thecompounds may be administered topically, orally, rectally,intravaginally intravenously, intraperitoneally, subcutaneously,intramuscularly or intranasally, or by other means known in the art, asappropriate for the effect sought. The drugs can also be administeredtransdermally using, for example, transdermal patches or transmucosallyvia sprays or other application. The drugs can be present in dosage unitform, for example, as a tablet, capsule or suppository, or formulated soas to be suitable for topical application (e.g., as a gel, cream, lotionor ointment). The compounds and compositions of the present inventioncan also be administered in liposomes, microemulsions, sprays, or viaany alternative delivery system.

Alternatively, the drugs can be present as a solution or suspension(e.g., sterile) suitable for administration by injection, inhalation,intranasally or drop wise to the eye or other sites as appropriate. Thedrugs of the invention can be prepared as a slow release formulationappropriate for internal or external use. Using techniques known in theart, they can also be trapped in or bound to a polymer, a solid support,a liposome or a gel.

Beta-alethine, TAUROX™ compounds and other compounds of Formula I, canbe administered together with additional active agents such hormones,vitamins, cytokines, enzyme regulators, regulatory macromolecules,regulatory thiols or other small molecules.

The compounds and compositions of the present invention are suitable fortherapeutic use in humans and for veterinary treatment of similarconditions affecting warm-blooded animals, such as dogs, cats, horses,birds and cattle and for reptiles, and fish. For such purposes, thecompounds can be administered in an analogous amount and manner to thosedescribed above for administration to humans.

Therapeutic administration of the beta-alethine and the TAUROX™compounds may be performed by methods known to those skilled in the artincluding orally, transmucosally, sublingually, parenterally,intravenous, intramuscular or subcutaneous routes, direct delivery intothe tumor, direct delivery into an affected body cavity by infusion, andoral or rectal administration.

A therapeutic dose, of the compounds of Formula I for use with themethods and compositions of the present invention, is an amount that iseffective to modulate cytokine production by immunocytes, or increasecytotoxic T lymphocytes, or activate T cells, or increase cellularimmunity, or increase PMBC proliferation. The amount of the compounds tobe used and the frequency of exposure for statistically significanteffects can be readily determined by one skilled in the art and willvary with the type of disease being treated or the cell type in the caseof ex vivo therapy, and the effect sought. The term “statisticallysignificant” is well known to those skilled in the art.

Cells can be grown or stored in the presence of the compounds using anyof a variety of available techniques, including growth on plastic orglass or other support (e.g., beads or hollow fibers), growth insuspension (e.g., in liquid or semisolid medium), growth in abioreactor, or storage in a frozen or dried state. Primary cultures orserial cultures, or otherwise, can be used.

The amount of the compound of the invention to be used and the frequencyof exposures or statistically significant effects can be readilydetermined by one skilled in the art and will vary with the cell type,the compound used and the effect sought. In determining optimumconcentrations, appropriate in vitro assays are run in the femtogram/mlto hundreds of mg/ml range.

Various aspects of the present invention are described in greater detailin the non-limiting Examples that follow.

Certain of the synthetic procedures for making small molecules that canbe used in the present invention are described by Knight et al, CancerResearch 54:5623 (1994) or in U.S. Pat. No. 4,218,404, U.S. Ser. No,08/733,174, or represent modifications thereof. These references areincorporated by reference herein in their entirety. In addition, thedisclosures of WO 92/00955 and PCT/US91/04725 are relevant here,including the portions therein that relate to syntheses, therapeuticregimens and cell culture treatment protocols, those regimens andprotocols being applicable to the drugs of the present invention. Thesereferences are also incorporated by reference herein in their entirety.

EXAMPLES Example I Beta-alethine Increases Ability of Animals toWithstand Environmental Stressors

Beta-alethine was administered to young chicks prior to exposure to aseries of environmental stressors that includes a live virus vaccine andchallenge with the bacterial pathogen E. coli, to test whetherbeta-alethine increases the longevity and basic health of the chicks.

On day one, 300 Peterson×Hubbard male broiler chicks were randomlyassigned to receive either beta-alethine only or an undisclosed positivecontrol; or no treatment prior to exposure. On day one, experimentalchicks received 2 ng per chick (approximately 50 ng/kg) s.c.beta-alethine. The positive control group received 10 μg/chick of anundisclosed compound and negative controls received no drugs. On day 8,a Newcastle disease live virus vaccine was administered by injection toboth positive and negative controls and to experimental chicks. Therewere 45 chicks in beta-alethine pen #2 and 50 in all other pens. On Day11, the chicks were stressed by simultaneous food withdrawal for 8hours, temperature extremes (95° F. at 6:30 am and 68° F. at 2:30 pm),and aerosol exposure to E. coli 19B. Temperature stress continuedthrough day 14. On day 18, all pens of chicks were evaluated for weightgain and feed efficiency; mortality was recorded throughout the study.

The mortality rate was lower in beta-alethine-treated chicks beginningon day 7 than in negative controls receiving no drugs (0% vs. 3%), andit continued to be lower throughout the experiment. In general, thebeta-alethine groups were similar to the positive controls. Survivalanalysis of mortality through day 16 indicated significant differences(p=0.016) between mortality of the negative controls and thebeta-alethine-treated chicks. The results show that 96% of thebeta-alethine-treated group survived to day 16, compared to only 85% ofthe untreated control group (the negative control group). Mortality dueto all causes of death through day 16 are displayed in Table I.

On days 17 and 18, 5 chicks in one beta-alethine pen died, resulting ina non-significant advantage at the end of study. We believe that theremay have been a technical failure that resulted in these 5 deaths.Alternatively, it is possible that the protective effect ofbeta-alethine lasts about 2 weeks rather than the 18 days of the study.

TABLE I Cumulative deaths by test day 18 Treatment day 18, # dead (# ofchicks) # dead from all causes of death from e. coli day: 5 7 8 11 12 1314 15 16 17 18 infection BT (n = 50) #1 0 0 0 1 1 1 1 1 1 1 2 1 BT (n =45) #2 0 0 0 0 1 1 1 1 3 6 8 8 pos. control (n = 50) 0 0 0 0 0 2 2 3 4 44 4 pos. control (n = 50) 1 1 3 3 3 3 3 3 3 4 4 1 neg. control (n = 50)0 1 1 1 1 5 5 5 5 5 5 4 neg. control (n = 50) 0 2 3 3 3 7 7 9 10 11 11 8n = number of chicks.

A similar statistically significant (p=0.044) reduction in the number ofdeaths attributed to colibacillosis (i.e., E.coli challenge) in thebeta-alethine -treated group compared to negative controls measured onday 16. Deaths were attributed to colibaccilosis if the death occurredafter exposure and the air sac culture was positive. Thus, all measuresof mortality were reduced by treatment with Beta-alethine. Survival inthe positive control group was similar to that observed for thebeta-alethine-treated group, but slightly (and nonsignificantly) worseat most time.

TABLE II Beta-alethine (BT) Reduces All Causes of Death Type ofMortality Evidence Early death, prior to Nonsignificant trend (p = .2):fewer deaths challenge in the beta-alethine group prior to day 11. (Seeleft side of table _(—) Death after challenge with Survival analysisthrough day 16 p = .044 E. coli (see table I), for those with E. coliinfections Total mortality Survival analysis through day 16 p = .016(see table I)

TABLE III Survival (% Alive) Day Beta-alethine Untreated Control 6  100% 100% 8 100  96 10 99 96 12 98 96 14 98 88 16 96 85Feed Efficiency and Deliverable Weight Ratio

Beta-alethine significantly increased conversion of chicken feed tochicken weight. The increased conversion is indicated by lower feedefficiency values which means that less food is needed to increaseweight. Feed efficiency is an estimate of the units of food used by livechicks to produce a unit of chicken weight. In all cases, weight andfood consumption is measured by weighing the whole pen and all feed.Only the dead chicks are individually weighed. F.E.=Pounds foodconsumed, ((total final weight of live chicks minus start weight at day0)+total weight of dead birds. The feed efficiency calculation adds theweight of the dead chicks to the total weight of the live chicks inorder to adjust for the weight of the dead chicks. The lower the feedefficiency, the less food is required to produce a unit of chickenweight. The calculation does not reflect the food wasted by dead chicks,but does attempt to adjust for them. The results show that the feedefficiency of the beta-alethine-treated group was 7.9% lower relative tothe negative controls, and also somewhat lower than the positivecontrols (Table IV).

The deliverable weight ratio was calculated because it is similar tofeed efficiency, but it includes an adjustment for the food consumed(and wasted) by chicks that do not survive. D.W.=Pounds food consumed,(total final weight of live chicks minus start weight). The deliverableweight ratio includes the food consumed and the total resulting weightafter including all resources. This reflects the fact that dead chickswill have consumed food and required the same initial investment ofother resources as live chicks, but they do not contribute to the finaldeliverable pounds of chicken.

The results show that beta-alethine caused a 10.8% point improvement infinal deliverable weight ratio (lower values) relative to untreatedcontrols.

TABLE IV Beta-alethine Improves Feed Efficiency and Deliverable WeightRatio Group Feed Efficiency Deliverable Weight Ratio² beta-alethine (#1plus #2) 1.298 1.367 positive control 1.359 1.403 negative control 1.4091.532 Beta-alethine vs negative 7.9% 10.8% control % improvement

The results of this experiment shows that a single dose of 2 ng perchick (approximately 50 ng/kg) beta-alethine (BT) given subcutaneouslyon day one of the experiment protected against death increasing thegeneral health and well-being of the animals as is indicated by theirenhanced resistance to environmental stressors. Beta-alethine (BT)administered 5 days prior to vaccination with live Newcastle diseasevirus and 10 days prior to the challenge with E. coli, significantlydecreased mortality. The beta-alethine-treated group also exhibitedincreased weight, a lower feed efficiency and a higher deliverableweight ratio.

Example II

A second experiment was conducted using chicks from a different breederand exposing them to less environmental stress. Avian x Ross broilerchicks were randomly assigned to groups receiving BT or saline, eitherin ovo at 17 days of development (4 days before hatch) or s.c. at day ofhatch , with or without additional BT fed directly in water on days 4,8, 18 and 25. All chicks received their respective treatment again onday 14. The BT dose was with 2 pg per bird or 2 ng (approx 50 ng/kg);birds receiving additional BT in the drinking water were given 2 ng perbird. There were a total of 3840 chicks (60 per pen) in 8 experimentalconditions (including controls) with 8 repetitions of each. The resultsthrough day 14, were collected before the second injections. At day 14,there was little mortality and no differences between groups on anymeasure except feed efficiency, which was improved in some of the BTgroups. Specifically, administration of 2 ng BT in ovo resulted insignificantly greater conversion of feed to weight (lower efficiencyratios). S.c. administration of 2 ng BT was also significantly betterthan saline given in ovo, but the difference between that group and thes.c. saline administration was not significant.

TABLE V % Decrease in Feed Efficiency Ratios Caused by Beta-alethine %decrease over dose per bird, saline control** and route MEAN Signif.*S.D. saline #1 saline #2 saline in ovo #1 1.185 d 0.0154 n/a 2 pg BT inovo 1.181 d 0.0133 0.34 −0.34 2 ng BT in ovo 1.147 a*** 0.0146 3.21 55saline sc 1.163 bc 0.0157 n/a 2 pg BT sc 1.173 cd 0.0107 −0.89  2 ng BTsc 1.150 ab 0.0105 1.16 saline in ovo #2 1.177 cd 0.0111 n/a 2 ng BT inovo + 1.157 ab*** 0.0190 2.39 1.73 fed in water (2 ng weekly) *Noteregarding stastistical significance: Means within a row without a commonsuperscript are significantly different (P < 0.05) as determined byLeast Significant Difference. The small standard deviations indicatethat the mean is a good representation of the group values and that evensmall differences between groups are meaningful. **Lower values for feedefficiency are more desirable, as they indicate less food is needed forweight gain. Where there are two values, the first column is Saline inovo #1; the second is Saline in ovo #2. Groups treated s.c. have onlythe saline s.c. control. ***significantly different from all salinegroups.

All documents cited above are hereby incorporated in their entirety byreference. The entire contents of U.S. Provisional Appln. No.60/005,336, filed Oct. 17, 1995; and 60/075,966 and 60/085,474, are alsoincorporated herein in their entirety.

One skilled in the art will appreciate from a reading of this disclosurethat various changes in form and detail can be made without departingfrom the true scope of the invention.

1. A method of lowering feed efficiency in an animal, comprisingadministering to the animal an amount of a compound of Formula I

wherein: the group A is SO₃H or a pharmaceutically acceptable saltthereof or physiologically hydrolyzable derivative thereof; the group R¹is H, a linear or branched lower alkyl, an arylalkyl or an alkenyl; thegroup R² is H, a linear or branched lower alkyl, an alkenyl, anarylalkyl, an acyl, a carbonate ester, an allyloxy carbonyl, acycloalkoxycarbonyl, an unsubstituted arylalkoxycarbonyl or asubstituted arylalkoxycarbony; or the groups R¹ and R² taken togetherform, with the nitrogen to which to which they are attached, a 5 to 7membered ring; and the groups L¹ and L² are, independently, ahydrocarbon linking group, a cycloalkyl, or an interphenylene; with theproviso that the compound of formula I is not beta-alethine; whichamount is sufficient to reduce the amount of food required to increase aunit of weight in the animal.
 2. The method of claim 1 wherein the groupA is SO₃H or a pharmaceutically acceptable salt thereof orphysiologically hydrolyzable (C₁ to C₄)alkyl or arylalkyl ester thereof;the group R¹ is H, a linear or branched (C₁ to C₆)alkyl, a substitutedor unsubstituted phenyl(C₁ to C₄)alkyl or a (C, to C₆)alkenyl; the groupR² is H, a linear or branched (C₁ to C₆)alkyl, a (C₁ to C₆)arylakyl, asubstituted or unsubstituted (C₁ to C₄)alkenyl, acetyl, benzoyl orarylsufonyl, a (C₁ to C₇)alkoxycarbonyl, —OCOCH₂CH═CH₂, a (C₁ toC₈)cyclo(C₁ to C₈)alkoxycarbonyl, —OCOCH₂C₆H₅ or a substitutedarylalkoxycarbonyl wherein the substituent is a halogen, a nitro group,an amino group or a methoxyl group; or the groups R¹ and R² takentogether form, with the nitrogen to which to which they are attached, a5 to 7 membered ring; and the groups L¹ and L² are, independently, alinear or branched chain alkyl of the formula —(C_(n)H_(2n))— wherein nis 1 to 8, cycloalkyl of 3 to 8 carbon atoms, or an interphenylene.
 3. Amethod of increasing weight gain in an animal, comprising administeringto the animal an amount of a compound of Formula I

wherein: the group A is SO₃H or a pharmaceutically acceptable saltthereof or physiologically hydrolyzable derivative thereof; the group R¹is H, a linear or branched lower alkyl, an arylalkyl or an alkenyl; thegroup R² is H, a linear or branched lower alkyl, an alkenyl, anarylalkyl, an acyl, a carbonate ester, an allyloxy carbonyl, acycloalkoxycarbonyl, an unsubstituted arylalkoxycarbonyl or asubstituted arylalkoxycarbonyl; or the groups R¹ and R² taken togetherform, with the nitrogen to which they are attached, a 5 to 7 memberedring; and the groups L¹ and L² are, independently, a hydrocarbon linkinggroup, a cycloalkyl, or an interphenylene; with the proviso that thecompound of formula I is not beta-alethine; which amount is sufficientto reduce the amount of food required to increase weight gain in theanimal.
 4. The method of claim 3 wherein the group A is SO₃H or apharmaceutically acceptable salt thereof or physiologically hydrolyzable(C₁ to C₄)alkyl or arylalkyl ester thereof; the group R¹ is H, a linearor branched (C₁ to C₆)alkyl, a substituted or unsubstituted phenyl(C₁ toC₄)alkyl or a (C2 to C₆)alkenyl; the group R2 is H, a linear or branched(C₁, to C₆)alkyl, a (C₁ to C₆)alkenyl, a substituted or unsubstitutedphenyl(C₁ to C₄)alkyl, an acetyl, benzoyl or arylsufonyl, a (C₁ toC₇)alkoxycarbonyl, —OCOCH₂CH═CH₂, a (C₃ to C8)cyclo(C₁ toC₈)alkoxycarbonyl, —OCOCH₂C₆H₅ or a substituted arylalkoxycarbonylwherein the substituent is a halogen, a nitro group, an amino group or amethoxyl group; or the groups R¹ and R² taken together form, with thenitrogen to which they are attached, a 5 to 7 membered ring; and thegroups L¹ and L² are, independently, a linear or branched chain alkyl ofthe formula —(C_(n)H_(2n))— wherein n is 1 to 8; cycloalkyl of 3 to 8carbon atoms, or an interphenylene.
 5. A method of increasing theconversion of food to body weight in an animal, comprising administeringan amount of a compound of Formula I

wherein: the group A is SO₃H or a pharmaceutically acceptable saltthereof or physiologically hydrolyzable derivative thereof, the group R¹is H, a linear or branched lower alkyl, an arylalkyl or an alkenyl; thegroup R² is H, a linear or branched lower alkyl, an alkenyl, anarylalkyl, an acyl, a carbonate ester, an allyloxy carbonyl, acycloalkoxycarbonyl, an unsubstituted arylalkoxycarbonyl or asubstituted arylalkoxycarbonyl; or the groups R¹ and R² taken togetherform, with the nitrogen to which they are attached, a 5 to 7 memberedring; and the groups L¹ and L² are, independently, a hydrocarbon linkinggroup, a cycloalkyl, or an interphenylene; with the proviso that thecompound of formula I is not beta-alethine; which amount is sufficientto increase conversion of food to body weight.
 6. The method of claim 5wherein the group A is SO₃H or a pharmaceutically acceptable saltthereof or physiologically hydrolyzable (C₁ to C₄)alkyl or arylalkylester thereof, the group R¹ is H, a linear or branched (C₁ to C₆)alkyl,a substituted or unsubstituted phenyl(C₁ to C₄)alkyl or a (C2 toC₆)alkenyl; the group R² is H, a linear or branched (C₁ to C₆)alkyl, a(C₁ to C₆)alkenyl, a substituted or unsubstituted phenyl(C₁ to C₄)alkyl,an acetyl, benzoyl or arylsufonyl, a (C₁ to C₇)alkoxycarbonyl,—OCOCH₂CH═CH₂, a (C₃ to C₈)cyclo(C₁ to C₈)alkoxycarbonyl, —OCOCH₂C₆H₅ ora substituted arylalkoxycarbonyl wherein the substituent is a halogen, anitro group, an amino group or a methoxyl group; or the groups R¹ and R²taken together form, with the nitrogen to which they are attached, a 5to 7 membered ring; and the groups L¹ and L2 are, independently, alinear or branched chain alkyl of the formula —(C_(n)H_(2n))— wherein nis 1 to 8; cycloalkyl of 3 to 8 carbon atoms, or an interphenylene. 7.The method as in claim 5, wherein the animal is a livestock animal. 8.The method of claim 5, wherein the animal is human.
 9. A method oftreating or preventing weight loss associated with disease in an mammal,comprising administering an amount of a compound of Formula I

wherein: the group A is SO₃H or a pharmaceutically acceptable saltthereof or physiologically hydrolyzable derivative thereof; the group R¹is H, a linear or branched lower alkyl, an arylalkyl or an alkenyl; thegroup R² is H, a linear or branched lower alkyl, an alkenyl, anarylalkyl, an acyl, a carbonate ester, an allyloxy carbonyl, acycloalkoxycarbonyl, an unsubstituted arylalkoxycarbonyl or asubstituted arylalkoxycarbonyl; or the groups R¹ and R² taken togetherform, with the nitrogen to which they are attached, a 5 to 7 memberedring; and the groups L¹ and L² are, independently, a hydrocarbon linkinggroup, a cycloalkyl, or an interphenylene; with the proviso that thecompound of formula I is not beta-alethine; which amount is sufficientto treat or prevent weight loss.
 10. The method of claim 9 wherein thegroup A is SO₃H or a pharmaceutically acceptable salt thereof orphysiologically hydrolyzable (C₁ to C₄)alkyl or arylalkyl ester thereof;the group R¹ is H, a linear or branched (C₁ to C₆)alkyl, a substitutedor unsubstituted phenyl(C₁ to C₄)alkyl or a (C2 to C₆)alkenyl; the groupR² is H, a linear or branched (C₁ to C₆)alkyl, a (C₁ to C₆)alkenyl, asubstituted or unsubstituted phenyl(C₁ to C₄)alkyl, an acetyl, benzoylor arylsufonyl, a (C₁ to C₇)alkoxycarbonyl, —OCOCH₂CH═CH₂, a (C₃ toC₈)cyclo(C₁ to C₈)alkoxycarbonyl, —OCOCH₂C₆H₅ or a substitutedarylalkoxycarbonyl wherein the substituent is a halogen, a nitro group,an amino group or a methoxyl group; or the groups R¹ and R² takentogether form, with the nitrogen to which they are attached, a 5 to 7membered ring; and the groups L¹ and L² are, independently, a linear orbranched chain alkyl of the formula —(C_(n)H_(2n))— wherein n is 1 to 8;cycloalkyl of 3 to 8 carbon atoms, or an interphenylene.
 11. A method oftreating cachexia in an animal, comprising administering an amount of acompound of Formula I

wherein: the group A is SO₃H or a pharmaceutically acceptable saltthereof or physiologically hydrolyzable derivative thereof, the group R¹is H, a linear or branched lower alkyl, an arylalkyl or an alkenyl; thegroup R² is H, a linear or branched lower alkyl, an alkenyl, anarylalkyl, an acyl, a carbonate ester, an allyloxy carbonyl, acycloalkoxycarbonyl, an unsubstituted arylalkoxycarbonyl or asubstituted arylalkoxycarbonyl; or the groups R¹ and R² taken togetherform, with the nitrogen to which they are attached, a 5 to 7 memberedring; and the groups L¹ and L² are, independently, a hydrocarbon linkinggroup, a cycloalkyl, or an interphenylene; with the proviso that thecompound of formula I is not beta-alethine; which amount is sufficientto treat or prevent cachexia in an animal.
 12. The method of claim 11wherein the group A is SO₃H or a pharmaceutically acceptable saltthereof or physiologically hydrolyzable (C₁ to C₄)alkyl or arylalkylester thereof; the group R¹ is H, a linear or branched (C₁ to C₆)alkyl,a substituted or unsubstituted phenyl(C₁ to C₄)alkyl or a (C2 toC₆)alkenyl; the group R² is H, a linear or branched (C₁ to C₆)alkyl, a(C₁ to C₆)alkenyl, a substituted or unsubstituted phenyl(C₁ to C₄)alkyl,an acetyl, benzoyl or arylsufonyl, a (C₁ to C₇)alkoxycarbonyl,—OCOCH₂CH═CH₂, a (C₃ to C₈)cyclo(C₁ to C₈)alkoxycarbonyl, —OCOCH₂C₆H₅ ora substituted arylalkoxycarbonyl wherein the substituent is a halogen, anitro group, an amino group or a methoxyl group; or the groups R¹ and R²taken together form, with the nitrogen to which they are attached, a 5to 7 membered ring; and the groups L¹ and L² are, independently, alinear or branched chain alkyl of the formula —(C_(n)H_(2n))— wherein nis 1 to 8; cycloalkyl of 3 to 8 carbon atoms, or an interphenylene. 13.The method of claim 9 wherein the disease is anorexia nervosa, bulimia,AIDS, cancer, or Crohn's disease.
 14. A method of decreasing mortalityamong a population of livestock animals, comprising administering to theanimal an amount of a compound of Formula I

wherein: the group A is SO₃H or a pharmaceutically acceptable saltthereof or physiologically hydrolyzable derivative thereof; the group R¹is H, a linear or branched lower alkyl, an arylalkyl or an alkenyl; thegroup R² is H, a linear or branched lower alkyl, an alkenyl, anarylalkyl, an acyl, a carbonate ester, an allyloxy carbonyl, acycloalkoxycarbonyl, an unsubstituted arylalkoxycarbonyl or asubstituted arylalkoxycarbonyl; or the groups R¹ and R² taken togetherform, with the nitrogen to which they are attached, a 5 to 7 memberedring; and the groups L¹ and L² are, independently, a hydrocarbon linkinggroup, a cycloalkyl, or an interphenylene; with the proviso that thecompound of formula I is not beta-alethine; which amount is sufficientto decrease mortality in the population of livestock animals.
 15. Amethod of improving feed efficiency in an animal, comprisingadministering to the animal an amount of a compound of Formula I

wherein: the group A is SO₃H or a pharmaceutically acceptable saltthereof or physiologically hydrolyzable derivative thereof; the group R¹is H, a linear or branched lower alkyl, an arylalkyl or an alkenyl; thegroup R² is H, a linear or branched lower alkyl, an alkenyl, anarylalkyl, an acyl, a carbonate ester, an allyloxy carbonyl, acycloalkoxycarbonyl, an unsubstituted arylalkoxycarbonyl or asubstituted arylalkoxycarbonyl; or the groups R¹ and R² taken togetherform, with the nitrogen to which they are attached, a 5 to 7 memberedring; and the groups L¹ and L² are, independently, a hydrocarbon linkinggroup, a cycloalkyl, or an interphenylene; with the proviso that thecompound of formula I is not beta-alethine; which amount is sufficientto improve feed efficiency in the animal.
 16. A method of increasing theability of an animal to withstand environmental stressors selected fromthe group consisting of food deprivation, temperature changes andexposure to one or more pathogens, comprising administering to theanimal an amount of a compound of Formula I

wherein: the group A is SO₃H or a pharmaceutically acceptable saltthereof or physiologically hydrolyzable derivative thereof; the group R¹is H, a linear or branched lower alkyl, an arylalkyl or an alkenyl; thegroup R² is H, a linear or branched lower alkyl, an alkenyl, anarylalkyl, an acyl, a carbonate ester, an allyloxy carbonyl, acycloalkoxycarbonyl, an unsubstituted arylalkoxycarbonyl or asubstituted arylalkoxycarbonyl; or the groups R¹ and R² taken togetherform, with the nitrogen to which they are attached, a 5 to 7 memberedring; and the groups L¹ and L² are, independently, a hydrocarbon linkinggroup, a cycloalkyl, or an interphenylene; with the proviso that thecompound of formula I is not beta-alethine; which amount is sufficientto enable the animal to withstand environmental stressors.
 17. Themethod of claim 16, wherein the environmental stress is fooddeprivation.
 18. The method of claim 16, wherein the environmentalstress is temperature change.
 19. The method of claim 16, wherein theenvironmental stress is exposure to one or more pathogens.
 20. A methodof increasing production of a desired product selected from the groupconsisting of milk, meat, wool, caviar, feathers, fur and hoofs, by ananimal, comprising administering to the animal an amount of a compoundof Formula I

wherein: the group A is SO₃H or a pharmaceutically acceptable saltthereof or physiologically hydrolyzable derivative thereof; the group R¹is H, a linear or branched lower alkyl, an arylalkyl or an alkenyl; thegroup R² is H, a linear or branched lower alkyl, an alkenyl, anarylalkyl, an acyl, a carbonate ester, an allyloxy carbonyl, acycloalkoxycarbonyl, an unsubstituted arylalkoxycarbonyl or asubstituted arylalkoxycarbonyl; or the groups R¹ and R² taken togetherform, with the nitrogen to which they are attached, a 5 to 7 memberedring; and the groups L¹ and L² are, independently, a hydrocarbon linkinggroup, a cycloalkyl, or an interphenylene; with the proviso that thecompound of formula I is not beta-alethine; which amount is sufficientto increase production of a desired product.
 21. The method of claim 16,wherein the bird is a chicken.
 22. The method of claim 21, wherein thecompound is administered in ovo.
 23. The method of claim 21, wherein thecompound is administered subcutaneously.
 24. A method of preventing oneor more bacterial or viral diseases in an animal raised in crowdedliving conditions, comprising administering to the animal an amount of acompound of Formula I

wherein: the group A is SO₃H or a pharmaceutically acceptable saltthereof or physiologically hydrolyzable derivative thereof, the group R¹is H, a linear or branched lower alkyl, an arylalkyl or an alkenyl; thegroup R² is H, a linear or branched lower alkyl, an alkenyl, anarylalkyl, an acyl, a carbonate ester, an allyloxy carbonyl, acycloalkoxycarbonyl, an unsubstituted arylalkoxycarbonyl or asubstituted arylalkoxycarbonyl; or the groups R¹ and R² taken togetherform, with the nitrogen to which they are attached, a 5 to 7 memberedring; and the groups L¹ and L² are, independently, a hydrocarbon linkinggroup, a cycloalkyl, or an interphenylene; with the proviso that thecompound of formula I is not beta-alethine; which amount is sufficientto prevent one or more of said diseases.
 25. The method as in claim 24,wherein the compound is carbobenzoxy beta-alanyl taurine.